CJ-023,423 (Grapiprant) a Potential Novel Active Compound with Antihyperalgetic Properties for Veterinary Patients

American Journal of Animal and Veterinary Sciences

Original Hypotheses Paper CJ-023,423 (Grapiprant) a Potential Novel Active Compound with Antihyperalgetic Properties for Veterinary Patients

Mario Giorgi

Department of Veterinary Sciences, University of Pisa, Via Livornese (lato monte), San Piero a Grado, Italy

Article history Abstract: Companion animals are now living longer and so are more Received: 23-12-2014 commonly manifesting age- and pain-related disease. Nonsteroidal anti- Revised: 26-12-2014 inflammatory drugs are the most used drug in osteoarthritis and Accepted: 31-12-2014 inflammatory pain of various aetiologies. Despite their safety profiles

have been amended from the COX-non selective to the COX-2 selective Email: [email protected] inhibitor class, some adverse effects are still of concern especially in long term treatments. One prostaglandin (PG) downstream from the cyclooxygenase enzyme, PGE2, has been recognized as a pivotal mediator of pain and inflammation. The actions of PGE2 are produced by its interaction with four G-protein coupled receptors (EP1, EP2, EP3 and EP4). The EP4 receptor mediates PGE2-elicited sensitization of sensory neurons and studies have demonstrated that EP4 is a major receptor in mediating pain associated with both rheumatoid and osteoarthritis and in inflammation. CJ-023,423 (grapiprant) is a competitive antagonist of human and rat prostanoid EP4 receptors, under development for the control of pain and inflammation associated with osteoarthritisfor use in humans and dogs. A recent study has shown the good safety profile of this active ingredient in dogs. Despite this molecule is still far to be marketed because it pharmacokinetic/pharmacodynamics profile is need to be fully elucidated yet, it might be an interesting active ingredient for the veterinary medicine.

Keywords: Anti-Inflammatory, NSAID, EP4 Receptor, Novel Active Compound, Veterinary Medicine

Introduction have been identified. COX-1 is constitutively expressed throughout the body and it is thought to play an essential Companion animals are now living longer and so are role in normal gastrointestinal and renal function, more commonly manifesting age-related diseases of whereas COX-2 is induced in the presence of medical importance such as cancer, arthritis and inflammation. NSAIDs inhibit both isoforms and metabolic disorders. They also share other life style, inhibition of COX-1 is thought to cause the adverse similarities that make them more suitable animal models gastrointestinal effects such as gastric erosion, ulceration than many of the traditionally used laboratory animals and haemorrhage, whereas inhibition of COX-2 is that can have drug resistance profiles that are quite associated with the therapeutic effects of NSAIDs. Thus, different to those in humans (Giorgi, 2012). Most if not inhibition of PG synthesis by NSAIDs has demonstrated all these diseases are pain and inflammation associated. clear efficacy in the reduction of pain and inflammation Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and and also has been shown to have putative effects beyond selective Cyclooxygenase (COX)-2 inhibitors are pain, including gastrointestinal and renal effects. These mainstays of the pharmacopoeia for the treatment of effects have been shown to be more severe in several signs and symptoms of osteoarthritis and inflammatory animal species rather than in human beings (Khan and pain of various etiologies. McLean, 2012). Selective COX-2 inhibitors were Their mechanism of action is to decrease designed to prevent those adverse effects mediated by prostaglandin (PG) synthesis by inhibiting COX inhibition of COX-1 (Zhang et al ., 1997; Hinz and Brune, activities. Two isoforms of COX, COX-1 and COX-2, 2002), but prolonged use of COX-2-selective inhibitors

Mario Giorgi / American Journal of Animal and Veterinary Sciences 2015, 10 (2): 53.56 DOI: 10.3844/ajavsp.2015.53.56 may, as with NSAIDs, confer a risk of cardiovascular physiological functions (Coleman et al ., 1994). EP1 is events, including hypertension, edema, heart attack and coupled to intracellular Ca 2+ mobilization, EP2 and EP4 stroke (Graham et al ., 2005; Lenzer, 2005; Solomon et al ., are coupled to stimulation of adenylate cyclase via Gs 2005). The cause of the adverse cardiovascular effects protein and EP3 is coupled to inhibition of adenylate remains unclear, but it may include an imbalance in cyclase via Gi protein. Studies performed either in mutant prostacyclin and thromboxane levels in the mice lacking the individual PG receptors (Stock et al ., endothelium (Bing and Lomnicka, 2002) and blockade 2001) or with synthetic EP receptor agonist/antagonist of prostanoid actions on renal function (Nasrallah and (Nakayama et al ., 2002) have not yet provided a coherent Hebert, 2005). Despite the COX-2 selective inhibitors picture of which EP receptors are responsible for of second generation have displayed reduced inflammatory pain. Recently it has been reported that EP4 knockdown with intrathecally delivered short hairpin RNA cardiovascular effects and so far they have never been attenuates inflammation-induced thermal and mechanical reported in animal species, they still remain a concern behavioral hypersensitivity (Lin et al ., 2006), suggesting for long lasting therapies (Kim and Giorgi, 2013). that EP4 is a potential target for the pharmacological Identification of new therapeutic targets treatment of inflammatory pain. However, developing downstream of COX may provide an opportunity for subtype-selective EP receptor antagonists has been the development of new analgesics that interfere with difficult because of the existence of multiple PG receptor prostanoid proinflammatory and pronociceptive actions with less gastrointestinal, renal and subtypes and the lack of the selectivity of synthetic PG cardiovascular risk. analogs. Thus, defining the contribution of EP receptor One PG downstream from the cyclooxygenase subtype to pain sensitization on the basis of available enzyme, PGE2, has long been recognized as a pivotal antagonists remains elusive. Nowadays, pets are treated mediator of pain and inflammation (Dannhardt and as members of the family and pet owners demand the Kiefer, 2001). The pathological and homeostatic effects same level of care they expect for themselves. This of PGE2 are mediated via a family of G protein-coupled change in attitude has resulted in a push for the receptor subtypes, designated EP1–4 (Fig. 1). These development of more effective and innovative veterinary receptor subtypes are distinguished by their distinct therapies (Giorgi, 2012; Giorgi and Owen, 2012a; pattern of tissue distribution, signaling pathways and 2012b; Giorgi and Yun, 2012; Lee et al ., 2014).

Fig. 1. Phospholipids cascade process involved in inflammation. Target points where diverse drugs can act are indicated

54 Mario Giorgi / American Journal of Animal and Veterinary Sciences 2015, 10 (2): 53.56 DOI: 10.3844/ajavsp.2015.53.56

Is hence critical that the research in veterinary References pharmacology is aimed to find out new active ingredients with good safety profile and efficacy. Bing, R.J. and M. Lomnicka, 2002. Why do cyclo- One of the new promising molecules that has been oxygenase-2 inhibitors cause cardiovascular events? testing with this purpose is the CJ-023,423 (N-[({2-[4- J. Am. Coll. Cardiol., 39: 521-522. (2-ethyl-4,6-dimethyl-1H-imidazo [4, 5-c] pyridin-1-yl) DOI: 10.1016/S0735-1097(01)01749-1 phenyl] ethyl}amino) carbonyl]-4-methylbenzen Coleman, R.A., S.P. Grix, S.A. Head, J.B. Louttit and A. esulfonamide), a novel, potent and selective EP4 Mallett et al ., 1994. A novel inhibitory prostanoid antagonist (Nakao et al ., 2007). receptor in piglet saphenous vein. Prostaglandins, CJ-023,423 (also named grapiprant) is highly selective for the human EP4 receptor compared with 47: 151-168. DOI: 10.1016/0090-6980(94)90084-1 other human prostanoid receptors (i.e., EP1, EP2, EP3, Dannhardt, G. and W. Kiefer, 2001. Cyclooxygenase prostaglandin D, F and I receptors and tromboxan A inhibitors-current status and future prospects. Eur. J. receptor). Grapiprant was discovered in 2007 and it Med. Chem., 36: 109-126. showed a competitive antagonist of human and rat DOI: 10.1016/S0223-5234(01)01197-7 prostanoid EP4 receptors with similar potency (pA2 = Giorgi, M. and H. Owen, 2012a. Mirtazapine in 8.3±0.03 and 8.2±0.2 nM, respectively). In addition it veterinary medicine a pharmacological rationale for was at least 200 times more selective over other human prostanoid receptors. The in vivo pharmacological its application in chronic pain. Am. J. Anim. Vet. antagonism of EP4 receptor with grapiprant produces Sci., 7: 42-47. DOI: 10.3844/ajavsp.2012.42.47 antihyperalgesic effects in rat models of inflammatory Giorgi, M. and H. Owen, 2012b. Flupirtine: A human pain, suggesting that inflammatory pain can be treated by drug with potential for use in the veterinary field. targeting a single PG receptor subtype EP4 (Nakao et al ., Am. J. Anim. Vet. Sci., 7: 213-217. 2007). Orally administrated CJ-023,423 reduced DOI: 10.3844/ajavsp.2012.213.217 inflammatory pain such as carrageenan-induced Giorgi, M. and H.I. Yun, 2012. Pharmacokinetics of mechanical hyperalgesia and CFA-induced weight- bearing deficit in rats. Grapiprant is now under mirtazapine and its main metabolites in Beagle development for use in humans and dogs for the control dogs: A pilot study. Vet. J., 192: 239-241. of pain and inflammation associated with osteoarthritis. DOI: 10.1016/j.tvjl.2011.05.010 Most of data are protected but recently a short abstract Giorgi, M., 2012. Veterinary pharmacology: Is it still has shown the good safety profile of this active pharmacology’s Cinderella? Clin. Exp. Pharmacol., ingredient in dogs. 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